N-(dialkylamino)methylene)-substituted pyrazolo(1,5-a)-pyrimidine-3-carboxamides and N-(dialkylamino)methylene-substituted-4,5-dihydropyrazolo-(1,5-a)-pyrimidine-3-carboxamides

ABSTRACT

Novel N-((dialkylamino)methylene)-substituted-pyrazolo(1,5-a)pyrimidine-3-ca rboxamide and N-((dialkylamino)methylene)-substituted-4,5-dihydropyrazolo-(1,5-a)-py rimidine-3-carboxamide compounds are disclosed which are useful as neurotropic and/or anxiolytic and/or anti-hypertensive agents in mammals.

This is a divisional of application Ser. No. 07/468,448, filed Jan. 22,1990, now U.S. Pat. No. 5,059,691.

The present invention relates to new organic compounds and moreparticularly it relates to novelN-((dialkylamino)methylene)-substituted-pyrazolo-(1,5-a)-pyrimidine-3-carboxamideand toN-((dialkylamino)methylene)-substituted-4,5-dihydropyrazolo-(1,5-a)-pyrimidine-3-carboxamidecompounds which are useful as neurotropic agents, anxiolytic agentsand/or anti-hypertensive agents in mammals.

BACKGROUND OF THE INVENTION

Various medicinal agents have been employed in the treatment of personssuffering from nervousness, anxiety and hypertension, as well ascognitive disorders.

Denzel et al, U.S. Pat. No. 4,072,681, discloses 3,7-dihydro- and1,7-dihydro-4H-pyrazolo (4',3':5,6)pyrido(4,3-d)pyrimidin-4-ones whichhave the general formula (I): ##STR1## wherein R¹ is hydrogen, loweralkyl or phenyl; R², R⁴ and R⁵ each is hydrogen or lower alkyl; and R³is hydrogen, lower alkyl, phenyl, substituted phenyl, phenyl-lower alkylor di(lower alkyl)-amino-lower alkyl. These compounds are said toexhibit both anti-inflammatory properties and central nervous systemdepressant activity.

Dusza et al, U.S. Pat. No. 4,281,000 discloses substitutedpyrazolo(1,5-a)pyrimidines of the general formula (II): ##STR2## whereinR¹ is hydrogen or alkyl having from 1 to 3 carbon atoms; R₂ is selectedfrom the group consisting of ##STR3## wherein R' is hydrogen or alkylhaving from 1 to 3 carbon atoms; R₃ is hydrogen, fluoro, chloro, bromo,cyano, cyanomethyl, carbamoyl or alkyl having from 1 to 3 carbons atoms;and R₄ is selected from the group consisting of hydrogen, fluoro,chloro, bromo, formyl, carboxyl, cyano, hydroxymethyl,N-hydroxyformimidoyl, alkyl having from 1 to 3 carbon atoms and moietiesof the formulae: ##STR4## where R is alkyl having from 1 to 3 carbonatoms. The disclosed compounds are said to exhibit anxiolytic activity.

Dusza et al, U.S. Pat. No. 4,178,449 discloses substitutedpyrazolo(1,5-a) pyrimidines and imidazo(1,5-a) pyrimidines of thegeneral formulae (III) and (IV) respectively: ##STR5## wherein R₁ ishydrogen or alkyl having from 1 to 3 carbon atoms; R₂ is selected fromthe group consisting of phenyl, ortho-trifluoromethylphenyl,meta-trifluoromethylphenyl and meta-methoxyphenyl; R₃ is hydrogen,fluoro, chloro, bromo, cyano, cyanomethyl, carbamoyl or alkyl havingfrom 1 to 3 carbon atoms; and R₄ is selected from the group consistingof hydrogen, fluoro, chloro, bromo, formyl, carboxyl, cyano,hydroxymethyl, N-hydroformimidoyl, alkyl having from 1 to 3 carbon atomsand moieties of the formulae: ##STR6## where R is alkyl having from 1 to3 carbon atoms.

SUMMARY OF THE INVENTION

The present invention relates to new organic compounds and moreparticularly is concerned with N-((dialkylamino)methylene)substitutedpyrazolo(1,5-a) pyrimidine-3-carboxamides andN-((dialkylamino)methylene)substituted-4,5-dihydropyrazolo(1,5-a)pyrimidine-3-carboxamidesuseful as neurotropic agents, anxiolytic agents and/or antihypertensiveagents in mammals. The compounds of the present invention may berepresented by the following structural formula: ##STR7## wherein - - -may represent the presence of a double bond between the N⁴ and C⁵position, Va, or the absence of a double bond between the N⁴ and C⁵position and a hydrogen atom bonded to the N⁴ position, Vb; R₁, R₃, R₄and R₅ may be the same or different and are selected from hydrogen or C₁to C₃ alkyl and R₂ is selected from the group consisting of hydrogen,3-pyridinyl, 4-pyridinyl and ##STR8## (where R₆ and R₇ may be the sameor different and are selected from the group consisting essentially ofhydrogen, halogen, C₁ to C₃ alkyl and trifluoromethyl), R₈ and R₉ may bethe same or different and are selected from C₁ to C₃ alkyl and wherehalogen is selected from chlorine, bromine and fluorine.

A preferred embodiment of the present invention may be represented bythe following structural formula: ##STR9## wherein - - - may representthe presence of a double bond between the N⁴ and C⁵ position, Va, or theabsence of a double bond between the N⁴ and C⁵ position and a hydrogenatom bonded to the N⁴ position, Vb; R₁, R₃, R₄ and R₅ may be the same ordifferent and are selected from hydrogen or C₁ to C₃ alkyl and R₂ isselected from the group consisting of hydrogen, 3-pyridinyl, 4-pyridinyland ##STR10## (wherein R₆ and R₇ may be the same or different and areselected from the group consisting essentially of hydrogen, halogen, C₁to C₃ alkyl and trifluoromethyl) and where halogen is selected fromchlorine, bromine and fluorine.

The present invention also includes novel compositions of mattercontaining the above-defined compounds which are useful as neurotropicagents, anxiolytic agents and/or antihypertensive agents in mammals andthe methods for treating cognitive and related neural behavioralproblems, anxiety and/or hypertension in mammals therewith. The presentinvention also includes a process for the chemical synthesis of thenovel compounds disclosed herein.

DETAILED DESCRIPTION OF THE INVENTION

The novel compounds of the present invention are obtainable as colorlessto yellow crystalline materials having characteristic melting points andabsorption spectra. They are generally soluble in organic solvents suchas lower alkanols, chloroform, tetrahydrofuran, N,N-dimethylformamide,dichloromethane, acetone and the like but are generally insoluble inwater.

The novelN-((dialkylamino)methylene)-substituted-pyrazolo(1,5-a)pyrimidine-3-carboxamideandN-((dialkylamino)methylene)substituted-4,5-dihydropyrazolo(1,5-a)-pyrimidine-3-carboxamidecompounds of the present invention may be readily prepared as set forthin the following general reaction schemes:

(a) reacting a compound of the formula: ##STR11## wherein R₁, R₂, R₃ andR₄ are as defined above with an acid to produce a compound of theformula ##STR12## wherein R₁, R₂, R₃ and R₄ are as defined above; andeither

(b) reacting the product of step (a) with a compound of the formula##STR13## wherein R₅, R₈ and R₉ are as defined above and R₁₀ is a C₁ toC₃ alkyl group or a C₁ to C₆ cycloalkyl group to produce a compound ofthe formula ##STR14## wherein R₁, R₂, R₃, R₄, R₅, R₈, R₉ and R₁₀ are asdefined above; or

(c)(i) reacting the product of step (a) with selective reducing agentreagent to produce a compound of the formula ##STR15## wherein R₁, R₂,R₃ and R₄ are as defined above; and (c)(ii) reacting the product of step(c)(i) with a compound of the formula ##STR16## wherein R₅, R₈, R₉ andR₁₀ are as defined above to produce a compound of the formula ##STR17##wherein R₁, R₂, R₃, R₄, R₅, R₈ and R₉ are as defined above.

In a preferred embodiment the compounds of the present invention may beprepared by the following preferred reaction scheme. ##STR18## whereinR₁, R₂, R₃, R₄, R₅, R₈ and R₉ are as above defined and R₁₀ is C₁ to C₃alkyl or C₁ to C₆ cycloalkyl.

As shown hereinabove a pyrazolo(1,5-a)-pyrimidine-3-carbonitrile (4)(prepared in the manner described in U.S. Pat. Nos. 4,281,000; 4,236,005and 4,178,499) is stirred with concentrated sulfuric acid at roomtemperature for from 2-20 hours. The mixture is carefully poured ontoice and the precipitate is collected, neutralized with sodium hydroxide,ammonium hydroxide or saturated sodium bicarbonate and the like andwashed with water to obtain the correspondingpyrazolo(1,5-a)pyrimidine-3-carboxamide compound (3).

The carboxamide compound (3) is heated at the reflux temperature with anN,N-dialkyl carboxamide dialkyl acetal, such as N,N-dimethylformamidedimethyl acetal, N,N-dimethylformamide diethyl acetal orN,N-dimethylformamide dicyclohexyl acetal for 1-30 hours, and then iscooled. The solvent is evaporated in vacuo and the residue is purifiedby conventional means to obtain theN-((dialkylamino)methylene)-substituted pyrazolo(1,5-a)pyrimidine-3-carboxamide compounds Va, where R₅ is hydrogen. WhenN,N-dimethylacetamide dimethyl acetal is substituted forN,N-dimethylformamide dimethyl acetal in the above procedure thecompounds Va where R₅ is methyl are obtained.

Alternatively when the carboxamide (3) is reacted with sodiumcyanoborohydride or an equivalent selective reducing agent like lithiumaluminum hydride, or the like, by stirring in glacial acetic acid undernitrogen in an ice bath for approximately one hour, then at roomtemperature for from 1-12 hours, the resulting precipitate is collectedand washed with water. The solid is dissolved in an inert solvent suchas dichloromethane or acetonitrile and the like and washed withsaturated sodium bicarbonate solution.

Separation and evaporation of the organic phase gives the crudeN-((dialkylamino)methylene)substituted-4,5-dihydropyrazolo(1,5-a)pyrimidine-3-carboxamide product(2) which is recrystallized from a solvent such as isopropyl alcohol oracetonitrile and the like or from a mixture of solvents such asetherhexane, chloroform-methanol or N,N-dimethylformamideacetonitrileand the like. The 4,5-dihydro-3-carboxamide (2) is then heated at thereflux temperature with N,N-dimethylformamide dimethyl acetal,N,N-dimethylacetamide dimethyl acetal according to the procedurehereinabove described, to obtain theN-((dialkylamino)methylene)substituted-4,5-dihydropyrazolo(1,5-a)pyrimioine-3-carboxamide compounds Vb where R₅ is hydrogen or theN-((dialkylamino)methylene)substituted-4,5-dihydropyrazolo(1,5-a)pyrimidine-3-carboxamide compoundsVb where R₅ is methyl, respectively.

The novel compounds of the present invention possess the ability toenhance neural function in warmblooded animals affected by behavioralneurological problems including the cognitive deterioration associatedwith decreased neural function which occurs with cerebral insufficiency,aging, dementia, and similar conditions.

A useful in vivo test that measures how effectively central nervoussystem-acting drugs enhance survival in an hypoxic environment,presumably by improving the ratio of energy supply to demand is known asthe Hypoxic Survival Test. This test demonstrates the ability of thetest compounds relative to known parasympathomimetic agentphysostigmine. This test shows the enhanced survival of test animals inan hypoxic environment after treatment with drug as compared to salinetreated control animals without drug. Extensive testing has demonstratedthat under conditions of 10 percent oxygen, only 5-20 percent of controlmice (treated with saline) survive after 5 minutes, whereas 60-80percent of the physostigmine treated mice survive. Drugs are tested byintraperitoneally injecting groups of mice 30 minutes prior to placingthem in hypoxic mixture and measuring survival. The rationale of thistest is that drugs which enhance survival under hypoxic conditionswithout concomitant, depression or sedative side effects, may do so byenhancing energy metabolism, or by preserving normal brain functionunder conditions of reduced energy metabolism. Given the dependence ofthe brain on a constant supply of energy, drugs which have this propertymay have many far-reaching therapeutic indications, including recoveryfrom stroke and closed head injury, as well as reducing the deleteriouseffects of the aging central nervous system. For example, in aged andsenile demented patients, energy metabolism is known to be deficient,and is thought to contribute significantly to the neurochemical andneurophysiological dysfunctions of aging.

Groups of 20 Royal Hart mice (6 weeks of age) are injectedintraperitoneally with test compound (0.1-100 mg/kg) 30 minutes prior toplacing them in a hypoxic mixture (10 percent oxygen in 90 percentcarbon dioxide) and measuring survival after 5 minutes.

A separate group of 20 mice is injected intraperitoneally with salinesolution (0.01 cc/g of body weight) and processed as described above.

Still another group of 20 mice is injected intraperitoneally with 0.125mg/kg of physostigmine and processed as described above.

Results of this test on representative compounds of the presentinvention are Table I.

Another in vivo test associated with decreased neural function inmammals is the Passive-Avoidance Anoxic-Induced-Amnesia Test. This testis used to determine the attenuation of anoxic induced amnesia in micetreated with drug, as compared to saline treated control animals with nodrug.

A shock-motivated, single trial, step-through passive avoidanceprocedure is used. Groups of 25 Swiss-Webster, middle aged mice (9months of age) are placed singly in the front chamber of a 2-chamber boxand are allowed to voluntarily cross into the rear chamber. As soon asthe mouse enters the rear chamber, a door automatically traps the animaland a mild electric shock (0.4 mA for 4 seconds) is delivered to itsfeet. Following the foot shock, the mice are initially placed in ananoxic environment (0 percent oxygen) for 12 seconds, which quicklyinduces unconsciousness. They are then placed in a hypoxic environment(15 percent oxygen) for four minutes which prolongs the oxygen deprivedstate, maintaining unconsciousness. All testing is performed 24 hourslater, and in all cases the mice appear fully recovered from theprevious anoxic/hypoxic treatment. All test compounds are administeredintraperitoneally at a dose of 5-200 mg/kg, 30 minutes prior to trainingand testing. Control animals are injected intraperitoneally only withsaline at 0.01 cc/g of body weight.

The latency to enter the rear chamber is recorded for both training andtesting. Presumably, the more the animal remembers being shocked, thegreater it will inhibit going into the rear chamber and the higher willbe its latency to re-enter. An improvement of 30 percent over salinecontrol scores is considered active. The results of this test onrepresentative compounds of the present invention appear in Table II.

                  TABLE I                                                         ______________________________________                                        Hypoxic Survival Test                                                                              Dose     %                                               Compound             mg/kg    Survivors                                       ______________________________________                                         .sub.-- N-((Dimethylamino)methylene)-2-                                                           10       55                                              methyl-7-(4-pyridinyl)pyrazolo-                                               (1,5- -a)pyrimidine-3-carboxamide                                              .sub.-- N-((Dimethylamino)methylene)-7-                                                           25       80                                              (3-pyridinyl)pyrazolo(1,5- -a)                                                                     25       58                                              pyrimidine-3-carboxamide                                                                           25       42                                               .sub.-- N-((Dimethylamino)methylene)-2-                                                             0.1    45                                              methyl-7-phenylpyrazolo(1,5- -a)-                                                                  10       100                                             pyrimidine-3-carboxamide                                                                           100      97                                                                   200      95                                               .sub.-- N-((Dimethylamino)methylene)-2,                                                           100      42                                              5-dimethyl-7-phenylpyrazolo(1,5- -a)-                                         pyrimidine-3-carboxamide                                                       .sub.-- N-((Dimethylamino)methylene)-6-                                                           10       42                                              methyl-pyrazolo(1,5- -a)pyrimidine-                                                                50       40                                              3-carboxamide        100      62                                                                   200      45                                               .sub.-- N-((Dimethylamino)methylene)-4,5-                                                         50       75                                              dihydro-7-(3-(trifluoromethyl)                                                                     100      57                                              phenyl)pyrazolo-(1,5- -a)pyrimidine-                                          3-carboxamide                                                                 ______________________________________                                    

                  TABLE II                                                        ______________________________________                                        Passive-Avoidance Anoxic Induced-Amnesia Test                                                     Dose     %                                                Compound            mg/kg    Improvement                                      ______________________________________                                        N-((Dimethylamino)methylene)-7-                                                                   25       33                                               (3-pyridinyl)pyrazolo(1,5- -a)-                                                                   50       33                                               pyrimidine-3-carboxamide                                                       .sub.-- N-((Dimethylamino)methylene)-2-                                                           5       49                                               methyl-7-phenylpyrazolo(1,5- -a)                                                                  10       37                                               pyrimidine-3-carboxamide                                                                          25       66                                                                   50       66                                                .sub.-- N-(1-(Dimethylamino)ethylidene)-7-                                                       25       53                                               (3-pyridinyl)pyrazolo(1,5- -a)-                                                                   50       46                                               pyrimidine-3-carboxamide                                                       .sub.-- N-((Dimethylamino)methylene)-4,5-                                                        25       49                                               dihydro-7-(3-(trifluoromethyl)                                                                    50       57                                               phenyl)-pyrazolo(1,5- -a)pyrimidine-                                          3-carboxamide                                                                  .sub.-- N-((Dimethylamino)methylene)-4,5-                                                        50       66                                               dihydro-7-(3-pyridinyl)pyrazolo-                                                                  100      54                                               (1,5- -a)pyrimidine-3-carboxamide                                             ______________________________________                                    

Certain of the novel compounds of the present invention possess centralnervous system activity at non-toxic doses and as such are useful asanxiolytic agents. They produce certain responses in standard tests withlaboratory animals which are known to correlate well with relief ofanxiety in human beings. The compounds, when tested pharmacologically,are found to have a desirable wide spread between doses producinganxiolytic activity and toxic symptoms.

The anti-anxiety properties of the novel compounds of the presentinvention have been established in a test which indicates anxiolyticactivity by the measure of protection from convulsions resulting fromthe administration of pentylenetetrazole. Single or graded dose levelsof the test compounds were administered orally or intraperitoneally in a2 percent starch vehicle containing 0.5 percent v/v polyethylene glycoland one drop of Polysorbate 80, or distilled water and one drop ofPolysorbate 80 to groups of at least four rats. At 30 or 60 minutes, therats were treated intravenously with pentylenetetrazole at a dose of 23mg/kg of body weight. This dose is estimated to cause clonic seizures in99 percent of unprotected rats. The test compounds are considered activeif they protect 50 percent or more of the rats from clonic seizures.

It has been reported (R. T. Hill and D. H. Tedeschi, "Animal Testing andScreening Procedures in Evaluating Psychotropic Drugs" in "AnIntroduction to Psychopharmacology", pp 237-288 (Eds. R. R. Rech and K.E. Moore, Raven Press, New York, 1971)) that there is a high degree ofcorrelation between antagonism of pentylenetetrazole seizures in ratsand anti-anxiety effects in higher warm-blooded animals.

The results of this test on representative compounds of the presentinvention appear in Table III.

                  TABLE III                                                       ______________________________________                                        Protection Against Clonic Seizures                                            Caused by Pentylenetetrazole in Rats                                                              Dose       % of Rats                                      Compound            mg/kg      Protected                                      ______________________________________                                         .sub.-- N-((Dimethylamino)methylene)-7-                                                          50         50                                             (3-methylphenyl)pyrazolo(1,5- -a)                                             pyrimidine-3-carboxamide                                                       .sub.-- N-((Dimethylamino)methylene)-4,                                                          25         75                                             5-dihydro-7-(3-(trifluoromethyl)                                                                  25         88                                             phenyl)pyrazolo-(1,5- -a)pyrimidine-                                                                12.5     88                                             3-carboxamide                                                                 ______________________________________                                    

Another test used to assess anti-anxiety effects is a non-conditionedpassive avoidance procedure described by J. R. Vogel, G. Beer and D. E.Clody, "A Simple and Reliable Conflict Procedure for Testing AntianxietyAgents", Psychopharmacologia, 21, 1-7 (1971). A conflict situation wasinduced in rats by a modification of this method.

Groups of 8 naive, Wistar strain rats, weighing 200-240 g each, weredeprived of water for 48 hours. The test compounds were administered insingle or graded, oral doses, suspended in 2 percent starch with 55percent polyethylene glycol in distilled water and one drop ofPolysorbate 80. Control animals received the vehicle alone. At 60minutes each rat was placed in an individual clear plastic chamber. Tapwater was available ad libitum from a nipple located in a black box offthe main chamber. A 0.7 milliampere AC shocking current was establishedbetween the stainless steel grid floor and the tap. After 20 licks ofnon-shocked drinking, a 2 second shocking current was administered tothe rat. This ratio of 20 licks of non-shocked drinking followed by a 2second shock was continued for a total of 3 minutes. The number ofshocks taken by each rat during the 3 minute interval was recorded andcompared to a control group.

The test compounds are considered active if the number of shocksreceived by the test group is significantly higher than the controlgroup by the Mann-Whitney U test. That is, the test compounds areconsidered active if they result in the treated rat taking slightly morethan double the number of shocks that the untreated rat will take.Results of this in vivo test on a representative compound of the presentinvention given in Table IV.

                  TABLE IV                                                        ______________________________________                                        Conflict Procedure In Rats                                                                                Result                                                                Dose    (no. of shocks                                    Compound            mg/kg   per 3 min.)                                       ______________________________________                                         .sub.-- N-((Dimethylamino)methylene-                                                             25      22.9                                              4,5-dihydro-7-(3-trifluoro-                                                   methyl)-phenyl)pyrazolo(1,5- -a)                                              pyrimidine-3-carboxamide                                                      ______________________________________                                    

Still another test utilized for the determination of anxiolytic activityis the measurement of the ability of a test compound to inhibit thebinding of tritiated benzodiazepines to brain-specific receptors ofmammals. A modification of the method described by R. F. Squires, et al,Nature, 266, No. 21:732 (April, 1977) and H. Mosler, et al, Science,198:849 (1977) was employed.

Male albino rats (Wistar strain, weighing 150-200 g each) were used. Thetest compounds were solubilized in N,N-dimethylformamide, acetic acid,ethanol or hydrochloric acid.

Whole cortex of rats was homogenized gently in 20 volumes of ice-cold0.32 M sucrose, centrifuged twice at 1000 g for 10 minutes and thenrecentrifuged at 30,000 g for 20 minutes to produce a crude P₂-synaptosomal fraction. The P₂ -fraction was either: (1) resuspended intwice the original volume in hypotonic 50 mM Tris.HCl(pH 7.4), or (2)resuspended in one-half of the original volume in hypotonic 10 mMTris.HCL (pH 7.4) and frozen (-20° C.) until time of use. Frozen P₂preparations were thawed and resuspended in four times the originalhomogenizing volume at time of assay.

The binding assay consisted of 300 l of the P₂ -fraction suspension(0.2-0.4 mg protein), 100 l of test drug and 100 l of 3H-diazepam 91.5nM, final concentration) or 3H-flunitrazepam (1.0 nM, finalconcentration )which was added to 1.5 l of 50 mM Tris.HCl (pH 7.4).Non-specific binding controls and total binding controls received 100 mlof diazepam (3 M final concentration) and 100 l of deionized water,respectively, in place of the test compound. Incubation for 30 minutesproceeded in ice and was terminated by filtration, under vacuum, throughglass fiber filters. The filters were washed twice with 5 ml of ice-cold50 mM Tris.HCl (pH 7.4) and placed in scintillation vials. After dryingat 50°-60° C. for 30 minutes, 10 ml of diluent was added and theradioactivity determined in a scintillation counter.

Inhibition of binding was calculated by the difference between totalbinding and binding in the presence of test compound, divided by thetotal, times 100. Physiological activity can be shown by a test compoundthat inhibits 3H-benzodiazepine binding by 12 percent or more. Such invitro activity is biologically relevant when the test compound alsodemonstrates statistically significant anxiolytic activity through invivo studies.

The result of this in vitro test on representative compounds of thisinvention are given in Table V.

                  TABLE V                                                         ______________________________________                                        Inhibition of the Binding of .sup.3 H-Benzodiazepine                          to Brain-Specific Receptors of Rats                                           Compound                % Inhibition                                          ______________________________________                                         .sub.-- N-((Dimethylamino)methylene)-7-phenyl-                                                       28                                                    pyrazolo(1,5- -a)pyrimidine-3-carboxamide                                      .sub.-- N-((Dimethylamino)methylene)-7-(3-methyl-                                                    65                                                    phenyl)pyrazolo(1,5- -a)pyrimidine-3-                                         carboxamide                                                                    .sub.-- N-(Dimethylamino)methylene)-7-(3-tri-                                                        82                                                    fluoromethyl)phenyl)pyrazolo(1,5- -a)-                                        pyrimidine-3-carboxamide                                                       .sub.-- N-((Dimethylamino)methylene)-2-methyl-7-                                                     18                                                    phenylpyrazolo(1,5- -a)pyrimidine-3-                                          carboxamide                                                                    .sub.-- N-((Dimethylamino)methylene)-4,5-dihydro-                                                    17                                                    7-(3-trifluoromethyl)phenyl)pyrazolo-                                         (1,5- -a)pyrimidine-3-carboxamide                                              .sub.-- N-((Dimethylamino)methylene)-4,5-dihydro-                                                    32                                                    7-(3-pyridinyl)pyrazolo(1,5- -a)pyrimidine-                                   3-carboxamide                                                                 ______________________________________                                    

Certain of the novel compounds of the present invention are activehypotensive agents at non-toxic doses when administered to mammals.These compounds were tested for hypotensive activity by the method of P.S. Chan and D. W. Poorvin, Clinical and Experimental Hypertension, 1(6), 817-813 (1979). Male, 16 week old spontaneously hypertensive ratsof the Okamoto strain having an average mean arterial blood pressure of160±1.5 mm of mercury are used in the test. One to three rats are usedper test compound. A rat is dosed by gavage with a test compound,suspended in 2 percent pre-boiled starch at a concentration of50 mg/ml,at a dose of 100 mg/kg of body weight or less, with 0.9 percent sodiumchloride loading at a dose of 25 ml/kg of body weight. A secondidentical dose of the test compound, without sodium chloride loading isgiven 24 hours later. At 28 hours after the initial dose the meanarterial blood pressure is measured by the method of Chan and Poorvinvide supra. The procedure is repeated in a second and third rat whennecessary.

The results of this test on representative compounds of the presentinvention appear below in Table VI.

                  TABLE VI                                                        ______________________________________                                        Reduction of Mean Arterial Blood Pressure in                                  Spontaneously Hypertensive Rats                                                                       MABP/mmHg                                             Compound                (no. of rat)                                          ______________________________________                                         .sub.-- N-((Dimethylamino)methylene)-2-methyl-7-                                                     130(2)                                                (4-pyridinyl)pyrazolo(1,5- -a)pyrimidine-                                     3-carboxamide                                                                  .sub.-- N-((Dimethylamino)methylene)-4,5-dihydro-                                                    131(3)                                                7-(3-(trifluoromethyl)phenyl)pyrazolo-                                        (1,5- -a)pyrimidine-3-carboxamide                                              .sub.-- N-((Dimethylamino)methylene)-4,5-dihydro-                                                    113(1)                                                7-(3-pyridinyl)pyrazolo(1,5- -a)pyrimidine-                                   3-carboxamide                                                                 ______________________________________                                    

The novel compounds of the present invention have been found to beuseful as agents for the treatment of cognitive and related neuralbehavioral problems in mammals when administered in amounts ranging from5 mg to about 200 mg/kg of body weight per day. A preferred dosageregimen for optimum results would be from about 10 mg to about50 mg/kgof body weight per day and such dosage units are employed so that atotal of from about 700 mg to about 3.5 g of the active compound for asubject of about 70 kg of body weight are administered in a 14 hourperiod.

Certain of the novel compounds of the present invention have been foundto be useful for meliorating anxiety in mammals when administered inamounts ranging from about 0.5 mg to about 100 mg/kg of body weight perday. A preferred dosage regimen for optimum results would be from about1.0 mg to about 50 mg/kg of body weight per day, and such dosage unitsare employed so that a total of from about 700 mg to about 3.5 g of theactive compound for a subject of about 70 kg of body weight areadministered in a 24 hour period.

Certain of the novel compounds of the present invention have been foundto be highly useful for lowering elevated blood pressure in mammals whenadministered in amounts ranging from 2.0 mg to about 100 mg/kg of bodyweight per day. A preferred dosage regimen for optimum results would befrom about 50 mg to about 750 mg per dose. Such dosage units areemployed so that a total of from about 200 mg to about 3.0 g of theactive compound for a subject of about 70 kg of body weight areadministered in a 24 hour period.

The hereinabove described dosage regimen for treating neural behavioralproblems, meliorating anxiety and lowering elevated blood pressure inmammals may be adjusted to provide the optimum therapeutic response. Forexample, several divided doses may be administered daily or the dose maybe proportionally reduced as indicated by the exigencies of thetherapeutic situation. A decided practical advantage is that theseactive compounds may be administered in any convenient manner such as bythe oral, intravenous, intramuscular or subcutaneous routes.

The active compounds may be orally administered, for example, with aninert diluent or with an assimilable edible carrier, or they may beenclosed in hard or soft shell gelatin capsules, or they may becompressed into tablets or they may be incorporated directly with thefood of the diet. For oral therapeutic administration, these activecompounds may be incorporated with excipients and used in the form ofingestible tablets, buccal tablets, troches, capsules, elixirs,suspensions, syrups, wafers and the like. Such compositions andpreparations should contain at least 0.1 percent of active compound. Thepercentage of the compositions and preparations may, of course, bevaried and may conveniently be between from about 2 percent to about 60percent of the weight of the unit. The amount of active compound in suchtherapeutically useful compositions is such that a suitable dosage willbe obtained. Preferred compositions or preparations according to thepresent invention are prepared so that an oral dosage unit form containsbetween about 5 and 200 mg of active compound.

The tablets, troches, pills, capsules and the like may also contain thefollowing: A binder such as gum tragacanth, acacia, corn starch orgelatin; excipients such as dicalcium phosphate; a disintegrating agentsuch as corn starch, potato starch, alginic acid and the like; alubricant such as magnesium stearate; and a sweetening agent such assucrose, lactose or saccharin may be added or a flavoring agent such apeppermint, oil of wintergreen or cherry flavoring agent. When thedosage unit form is a capsule it may contain, in addition to materialsof the above type, a liquid carrier. Various other materials may bepresent as coatings or to otherwise modify the physical form of thedosage unit. For instance, tablets, pills or capsules may be coated withshellac, sugar or both. A syrup or elixir may contain the activecompound, sucrose as a sweetening agent, methyl and propylparabens aspreservatives, a dye and flavoring such as cherry or orange flavor. Ofcourse, any material used in preparing any dosage unit form should bepharmaceutically pure and substantially non-toxic in the amounts used.In addition, these active compounds may be incorporated into sustainedrelease preparations and formulations.

These active compounds may be administered parenterally orintraperitoneally. Solutions or suspensions of these active compounds asa free base or pharmacologically acceptable salt can be prepared inwater suitably mixed with a surfactant such as hydroxypropylcellulose.Dispersions can also be prepared in glycerol, liquid polyethyleneglycols and mixtures thereof in oils. Under ordinary conditions ofstorage and use, these preparations contain a preservative to preventthe growth of microorganisms.

The pharmaceutical forms suitable for injectable use include sterileaqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In all cases, the form must be sterile and must be fluid tothe extent that easy syringability exists. It must be stable under theconditions of manufacture and storage and must be preserved against thecontaminating action of microorganisms such as bacteria and fungi. Thecarrier can be a solvent or dispersion medium containing, for example,water, ethanol, polyol (e.g. glycerol, propylene glycol and liquidpolyethylene glycol), suitable mixtures thereof, and vegetable oils.

DESCRIPTION OF PREFERRED EMBODIMENTS

The invention will be described in greater detail in conjunction withthe following specific examples. They are not to be construed to limitthe claims in any manner whatsoever.

EXAMPLE 1 7-(3-Methylphenyl)pyrazolo(1,5-a) pyrimidine-3 -carbonitrile

A mixture of 50.0 g of 3-methylacetophenone and 60 ml ofN,N-dimethylformamide dimethylacetal is heated at reflux for 16 hours.The reaction mixture is then evaporated in vacuo to give an oil. The oilis treated with dichloromethane/hexane to crystallize 54.50 g of3-dimethylamino-3'-methylacrylophenone.

A stirred mixture of 10.82 g of 5-amino-4-pyrazolecarbonitrile and 18.92g of the preceding product in 50 ml of glacial acetic acid is heated atreflux for 7 hours. The reaction mixture is cooled, evaporated, and theresidue dissolved in dichloromethane and washed with a saturated sodiumbicarbonate solution. The organic layer is dried over anhydrous sodiumsulfate and passed through a short column of hydrous magnesium silicate,and then hexane is added to the eluate until crystallization occurs. Thesolid is collected by filtration and recrystallized fromdichloromethane-hexane to give 10.60 g of the desired product, mp161°-162° C.

EXAMPLE 2 2-Methyl-7-(4-pyridinyl)pyrazolo(1,5-a) pyrimidine-3-carbonitrile

A mixture of 6.1 g of 5-amino-3-methyl-4-pyrazole carbonitrile and 8.81g of 3-dimethylamino-1-(4-pyridinyl)-2-propen-1-one in 50 ml of glacialacetic acid is stirred and heated at reflux for 5 hours. The reactionmixture is cooled and the precipitate which forms is collected byfiltration and washed with water and a little dichloromethane to give asolid. The solid is partitioned between saturated sodium bicarbonate anddichloromethane. The organic layer is dried over anhydrous sodiumsulfate and passed through a short column of hydrous magensium silicate.The addition of hexane to the eluate crystallizes the product which iscollected by filtration to give 6.17 g of the desired product, mp220°-221° C.

EXAMPLE 3 2,5-Dimethyl-7-phenylpyrazolo(1,5-a) pyrimidine-3-carbonitrile

To a solution of 17.4 g of benzoylacetone in 100 ml of ethyl acetate isadded a solution of 7.35 g of pyrrolidine in 50 ml of ethyl acetate. Thereaction mixture is stirred at room temperature for 16 hours. Theprecipitated compound is collected by filtration to give 20.30 g of3-(1-pyrrolidinyl)crotonophenone.

A mixture of 4.88 g of 5-amino-3-methyl-4-pyrazolecarbonitrile and 8.61g of 3-(1-pyrrolidinyl)crotonophenone in 50 ml of glacial acetic acid isstirred and heated at reflux for 6 hours. The reaction mixture is cooledand the procedure described in Example 2 is then followed to obtain 7.77g of the desired product, mp 175°-177° C.

EXAMPLE 4 6-Methylpyrazolo(1,5-a)pyrimidine-3-carbonitrile

By the procedure described in Example 2, 5.40 g of5-amino-4-pyrazolecarbonitrile is reacted with 5.70 g of3-ethoxy-2-methylacrolein in 25 ml of glacial acid to give the desiredproduct as colorless prisms, mp 193°-194° C.

EXAMPLE 5 7-(3-Trifluoromethyl)phenylpyrazolo(1,5-a)pyrimidine-3-carboxamide

A mixture of 3.0 g of7-(α,α,α-trifluoro-m-tolyl)pyrazolo(1,5-a)pyrimidine-3-carbonitrile(prepared as described in U.S. Pat. No. 4,236,005) and 150 ml ofconcentrated sulfuric acid is stirred at room temperature for 4 hours.The solution is then carefully poured into ice water with stirring. Thewhite precipitate which forms is collected, washed with water and thenwith saturated sodium bicarbonate until it is neutral. The solid isheated with one liter of isopropyl alcohol and filtered. The white solidis then dried in vacuo to give the desired product as a colorless solid,mp 256°-258° C.

EXAMPLE 6 7-(2,5-Dichlorophenyl)-2-methylpyrazolo(1,5-a-)pyrimidine-3-carboxamide

A mixture of 31.0 g of 2',5'-dichloroacetophenone and 25 ml ofN,N-dimethylformamide dimethyl acetal is heated on a steam bath for 6hours, then evaporated to dryness in vacuo. The residue is slurried withhexane, and filtered to give 35.3 g of2',5'-dichloro-3-dimethylaminoacrylophenone as orange crystals, mp83°-85° C.

A mixture of 12.2 g of 3-amino-4-cyano-5-methyl-pyrazole and 24.4 g of2',5'-dichloro-3-dimethylaminoacrylophenone in 250 ml of glacial aceticacid is heated on a steam bath for 4 hours. The mixture is cooled andfiltered to give 21.28 g of7-(2,5-dichlorophenyl)-2-methylpyrazolo(1,5-a)pyrimidine-3-carbonitrileas off-white crystals.

21.28 g of the preceding product is dissolved in concentrated sulfuricacid and stirred for 5 hours. The solution is carefully poured onto ice.The precipitate which forms is collected by filtration, washed withwater and air dried to give the desired product as colorless crystals,mp 234°-236° C.

EXAMPLES 7-16

Additional pyrazolo(1,5-a)pyrimidine-3-carboxamides which are preparedfrom the corresponding pyrazolo(1,5-a)pyrimidine-3-carbonitriles in themanner described in Examples 5 are listed in Table VII.

The pyrazolo(1,5-a)pyrimidine-3-carbonitriles are prepared by theprocedures described in U.S. Pat. Nos. 4,178,449; 4,236,005; and4,281,000 by reacting the approximate 3-(dimethylamino)acrylophenoneintermediate with an appropriately substituted3-aminopyrazole-4-carbonitrile.

                                      TABLE VII                                   __________________________________________________________________________    Pyrazolo(1,5- -a)pyrimidine-3-carboxamides                                     ##STR19##                                                                    Example                                                                            Compound            R.sub.1                                                                          R.sub.2  R.sub.3                                                                          R.sub.4                                                                          MP °C.                      __________________________________________________________________________     7   7-Phenylpyrazolo(1,5- -a)pyrimidine-3- carboxamide                                                H                                                                                 ##STR20##                                                                             H  H    236-238.5                         8   2-Methyl-7-phenylpyrazolo(1,5- -a)pyrimi- dine-3-carboxamide                                      CH.sub.3                                                                          ##STR21##                                                                             H  H  233-235                             9   7-(3-Pridinyl)pyrazolo(1,5- -a)pyrimidine 3-carboxamide                                           H                                                                                 ##STR22##                                                                             H  H  285-236                            10   7-(4-Pyridinyl)pyrazolo(1,5- -a)pyrimi- dine-3-carboxamide                                        H                                                                                 ##STR23##                                                                             H  H  394-396                            11   7-(3-Fluorophenyl)pyrazolo(1,5- -a) pyrimidine-3-carboxamide                                      H                                                                                 ##STR24##                                                                             H  H  247-249                            12   2-Methyl-7-((3-trifluoromethyl)phenyl) pyrazolo(1,5- -a)pyrimidine-3-         carboxamide         CH.sub.3                                                                          ##STR25##                                                                             H  H  209.5-210.5                        13   7-(3-Methylphenyl)pyrazolo(1,5- -a) pyrimidine-3-carboxamide                                      H                                                                                 ##STR26##                                                                             H  H  228-229                            14   2-Methyl-7-(4-pyridinyl)pyrazolo (1,5- -a)-pyrimidine-3-carboxamide                               CH.sub.3                                                                          ##STR27##                                                                             H  H  286-288                            15    2,5-Dimethyl-7-phenylpyrazolo(1,5- -a) pyrimidine-3-carboxamide                                  CH.sub.3                                                                          ##STR28##                                                                             H  CH.sub.3                                                                         212-213                            16   6-Methylpyrazolo(1,5- -a)pyrimidine-3-                                                            H  H        CH.sub.3                                                                         H  251-253                                 carboxamide                                                              __________________________________________________________________________

EXAMPLE 174,5-Dihydro-7-(3-(trifluoromethyl)phenyl)-pyrazolo-(1,5-a)pyrimidine-3-carboxamide

A 10.0 g amount of7-(3-trifluoromethyl)phenyl)-pyrazolo(1,5-a)pyrimidine-3-carboxamide(prepared as described in Example 5) is stirred under nitrogen as asuspension in 120 ml of glacial acetic acid (cooled in an ice bath) andthen 5.5 g of sodium cyanoborohydride is added to the reaction mixturein portions, with an additional 80 ml of glacial acetic acid. After onehour of stirring in the ice bath the mixture is stirred at roomtemperature for 19 hours. The solution is evaporated to dryness, thenwater is added and the white precipitate which forms is collected byfiltration and washed with an aqueous saturated solution of sodiumbicarbonate, then with water. The solid is treated with 100 ml ofacetonitrile, then collected and dried to give 5.25 g of the desiredproduct which is recrystallized from acetonitrile, mp 157°-160° C.

EXAMPLE 184,5-Dihydro-7-(3-pyridinyl)pyrazolo(1,5a)-pyrimidine-3-carboxamide

A 20.0 g amount of 7-(3-pyridinyl)pyrazolo(1,5-a)-pyrimidine-3-carboxamide (prepared as described in Example 9) issuspended in 200 ml of glacial acetic acid under nitrogen with stirringat room temperature. Then 14.0 g of sodium cyanoborohydride is added inportions and the mixture is stirred for 3 hours. The mixture is thenallowed to stand at room temperature for 16 hours, and then the reactionmixture evaporated to dryness. Water is added to the residue followed bysaturated sodium bicarbonate until a pH of about 8.0 is achieved and agummy solid precipitated. The solid is collected by filtration and thendissolved in acetonitrile. Evaporation of the organic solvent gives 10.0g of a yellow solid (A). The aqueous filtrate above is evaporated todryness in vacuo and this residue is extracted with acetonitrile.Evaporation of the solvent gives a yellow gummy solid (B). The solids(A) and (B) are combined and triturated with isopropyl alcohol to give ayellow solid precipitate which is isolated and dried in vacuo to give61.9 g of the desired product which is then recrystallized fromisopropyl alcohol-acetonitrile, mp 182°-184° C.

EXAMPLE 19 7-(3-Fluorophenyl)-4,5-dihydropyrazolo(1,5-a)pyrimidine-3-carboxamide

To a stirred mixture of 136.3 g of7-(3-fluorophenyl)pyrazolo(1,5-a)pyrimidine-3-carboxamide (prepared asdescribed in Example 11) in one liter of glacial acetic acid at roomtemperature under nitrogen is added 83.6 g of sodium cyanoborohydride inportions. The mixture is stirred at room temperature for 16 hours. Thecrystals that form are collected by filtration and triturated withsaturated sodium bicarbonate until a pH of 7-8 is achieved. The crystalsare then filtered, washed with excess water and dried in vacuo to give63.0 g of the desired product of the example as cream colored crystals,mp 122°-125° C.

EXAMPLE 20N-((Dimethylamino)methylene)-7-phenylpyrazolo(1,5-a)-pyrimidine-3-carboxamide

A mixture of 600 mg of 7-phenylpyrazolo(1,5-a)-pyrimidine-3-carboxamide(Example 7), 5.0 ml of N,N-dimethylformamide dimethyl acetal and 25.0 mlof dichloromethane are heated on a steam bath for 2 hours with completesolution taking place. The solution is evaporated in vacuo to give asolid. The solid is then recrystallized from acetone to give 58 mg ofthe desired product as yellow needles, mp 198°-201.5° C.

EXAMPLE 21N-((Dimethylamino)methylene)-2-methyl-7-((3-trifluoromethyl)phenyl)pyrazolo(1,5-a)pyrimidine3-carboxamide

A mixture of 1.67 g of2-methyl-7-(3-trifluoromethyl)phenyl)pyrazolo(1,5-a)pyrimidine-3-carboxamide(Example 12) and 5.0 ml of N,N-dimethylformamide dimethyl acetal isheated on a steam bath for one hour to give a solution. The solution iscooled and the precipitate that forms is collected by filtration to give1.82 g of the desired product as pale yellow prisms, mp 174°-175.5° C.

EXAMPLE 22 N-((Dimethylamino)methylene)7-(3-methylphenyl)pyrazolo(1,5-a)pyrimidine-3-carboxamide

A mixture of 6.0 g of 7-(3-methylphenyl)pyrazolo(1,5-a)pyrimidine-3-carboxamide (Example 13) and 15 ml ofN,N-dimethylformamide dimethyl acetal is heated on a steam bath for 4hours to give a solution. The solution is evaporated in vacuo to give asolid. The solid is recrystallized twice from dichloromethane-hexane togive 4.70 g of the desired product as colorless crystals, mp 165°-166°C.

EXAMPLES 23-31

Additional N-((dimethylamino)methylene)pyrazolo(1,5-a)pyrimidine-3-carboxamide andN-((dimethylamino)methylene)-4,5-dihydropyrazolo(1,5-a)pyrimidine-3-carboxamideproducts are prepared from the correspondingpyrazolo(1,5-a)pyrimidine-3-carboxamide or the4,5-dihydropyrazolo(1,5-a)pyrimidine-3-carboxamide intermediatecompounds by heating with N,N-dimethylformamide dimethyl acetal in themanner described in Examples 20-22 and are listed in Table VIII.

                                      TABLE VIII                                  __________________________________________________________________________     .sub.-- N-((Dimethylamino)methylene)pyrazolo(1,5- -a)pyrimidine-3-carboxa    mides                                                                         and  .sub.-- N-((Dimethylamino)methylene)4,5-dihydropyrazolo(1,5- -a)         pyrimidine-3-carboxamides                                                     Example                                                                            Precursor                                                                           Compound               MP °C.                               __________________________________________________________________________    23   Example 5                                                                            .sub.-- N-((Dimethylamino)methylene)-7-(3-trifluoro-                                                156-158                                                methyl)phenyl)pyrazolo(1,5- -a)pyrimidine-3-                                  carboxamide                                                        24   Example 14                                                                           .sub.-- N-((Dimethylamino)methylene)-2-methyl-7-(4-                                                 198-200                                                pyridinyl)pyrazolo(1,5- -a)pyrimidine-3-                                      carboxamide                                                        25   Example 9                                                                            .sub.-- N-((Dimethylamino)methylene)-7-(3-pyridinyl)-                                               209-211                                                pyrazolo(1,5- -a)pyrimidine-3-carboxamide                          26   Example 8                                                                            .sub.-- N-((Dimethylamino)methylene)-2-methyl-7-                                                    150-152                                                phenylpyrazolo(1,5- -a)pyrimidine-3-carboxamide                    27   Example 15                                                                           .sub.-- N-((Dimethylamino)methylene)-2,5-dimethyl-7-                                                210-212                                                phenylpyrazolo(1,5- -a)pyrimidine-3-carboxamide                                                      (dec.)                                      28   Example 16                                                                           .sub.-- N-((Dimethylamino)methylene)-6-methyl-                                                      213-215                                                pyrazolo(1,5- -a)pyrimidine-3-carboxamide                          29   Example 6                                                                           7-(2,5-Dichlorophenyl)- .sub.-- N-((dimethylamino)-                                                  195-197                                                methylene-2-methylpyrazolo(1,5- -a)pyrimidine-                                3-carboxamide                                                      30   Example 17                                                                           .sub.--  N-((Dimethylamino)methylene)-4,5-dihydro-7-                                                133-135                                                (3-(trifluoromethyl)phenylpyrazolo(1,5- -a)-                                  pyrimidine-3-carboxamide                                           31   Example 18                                                                           .sub.-- N-((Dimethylamino)methylene)4,5-dihydro-7-                                                  132-135                                                (3-pyridinyl)pyrazolo(1,5- -a)pyrimidine-3-                                   carboxamide                                                        __________________________________________________________________________

EXAMPLES 32-34

Other N-((dimethylamino)methylene)pyrazolo(1,5-a)-pyrimidine-3-carboxamide and N-((dimethylamino)methylene)-4,5-dihydropyrazolo(1,5-a)pyrimidine-3-carboxamide productswhich are prepared from correspondingpyrazolo(1,5-a)pyrimidine-3-carboxamide or the4,5-dihydropyrazolo(1,5-a)pyrimidine-3-carboxamide intermediatecompounds by heating with N,N-dimethylformamide dimethyl acetal in themanner described in Examples 20-22 are listed in Table IX.

                  TABLE IX                                                        ______________________________________                                         .sub.-- N-((Dimethylamino)methylene)pyrazolo(1,5- -a)                        pyrimidine-3-carboxamides and  .sub.-- N-((Dimethylamino)                     methylene)-4,5-dihydropyrazolo(1,5- -a)pyrimidine                             3-carboxamides                                                                Example Presursor  Compound                                                   ______________________________________                                        32      Example 10  .sub.-- N-((Dimethylamino)methylene)-                                        7-(4-pyridinyl)pyrazolo(1,5- -a)                                              pyrimidine-3-carboxamide                                   33      Example 11 7-(3-Fluorophenyl)- .sub.-- N-((dimethyl-                                     amino)methylene)pyrazolo(1,5- -a)-                                            pyrimidine-3-carboxamide                                   34      Example 19 7-(3-Fluorophenyl)- .sub.-- N-((dimethyl-                                     amino)methylene)-4,5-dihydro-                                                 pyrazolo(1,5- -a)pyrimidine-3-                                                carboxamide                                                ______________________________________                                    

EXAMPLE 35N-((Dimethylamino)ethylidene)-7-(3-pyridinyl)pyrazolo(1,5-a)pyrimidine3-carboxamide

A mixture of 10.0 g of7-(3-pyridinyl)pyrazolo(1,5-a)pyrimidine-3-carboxamide (prepared asdescribed in Example 9) and 50.0 ml of N,N-dimethylacetamide dimethylacetal are heated at 120° C. for 2 hours. After cooling, the reactionmixture is evaporated in vacuo to give an oil. The oil is trituratedwith diethyl ether to separate a yellow solid. The solid is collected byfiltration, washed with ether, air dried, then dried in vacuo to give12.37 g of the desired product as a tan solid, mp 124°-127° C.

The above-mentioned patents and publications are incorporated herein byreference.

Many variations of the present invention will suggest themselves tothose skilled in this art in light of the above detailed description.All such obvious modifications are within the full intended scope of theappended claims.

We claim:
 1. A compound of the formula: ##STR29## wherein - - - mayrepresent the presence of a double bond between the N⁴ and C⁵ position,Va, or the absence of a double bond between the N⁴ and C⁵ position and ahydrogen atom bonded to the N⁴ position, Vb; R₁, R₃, R₄ and R₅ may bethe same or different and are hydrogen or C₁ to C₃ alkyl; R₂ is3-pyridinyl, 4-pyridinyl, or hydrogen; R₈ and R₉ may be the same ordifferent and are C₁ to C₃ alkyl; or a pharmaceutically acceptable saltthereof.
 2. A compound of the formula ##STR30## ##STR31## wherein - - -may represent the presence of a double bond between the N⁴ and C⁵position, Va, or the absence of a double bond between the N⁴ and C⁵position and a hydrogen atom bonded to the N⁴ position, Vb; R₁, R₃, R₄and R₅ may be the same or different and are hydrogen or C₁ to C₃ alkyl;and R₂ is hydrogen, 3-pyridinyl, or 4-pyridinyl; ##STR32## or apharmaceutically acceptable salt thereof.
 3. A compound as defined inclaim 1, which is N-((dimethylamino)methylene)-2-methyl-7-(4-pyridinyl)pyrazolo(1,5-a)pyrimidine-3-carboxamide.
 4. A compound as defined inclaim 1, which is N-((dimethylamino)methylene)-7-(3-pyridinyl)pyrazolo(1,5-a)pyrimidine-3-carboxamide.
 5. A compound as defined in claim 1,which is N-((dimethylamino)methylene)-6-methylpyrazolo(1,5-a)pyrimidine-3-carboxamide.
 6. A compound as defined in claim 1, which isN-((dimethylamino)methylene)-4,5-dihydro-7-3-pyridinyl)pyrazolo(1,5-a)pyrimidine-3-carboxamide.
 7. A compound as defined inclaim 1, which is N-((dimethylamino)ethylidene)-7-(3-pyridinyl)pyrazolo(1,5-a)pyrimidine-3-carboxamide.
 8. A method of lowering elevated bloodpressure in a warm-blooded animal which comprises administering to saidwarm-blooded animal a pharmacologically effective amount of a compoundof the formula: ##STR33## wherein - - - may represent the presence of adouble bond between the N⁴ and C⁵ position, Va, or the absence of adouble bond between the N⁴ and C⁵ position and a hydrogen atom bonded tothe N⁴ position, Vb; R₁, R₃, R₄ and R₅ may be the same or different andare hydrogen or C₁ to C₃ alkyl; R₂ is 3-pyridinyl, 4-pyridinyl, orhydrogen or ##STR34## where R₆ and R₇ may be the same or different andare hydrogen, halogen, C₁ to C₃ alkyl or trifluoromethyl; R₈ and R₉ maybe the same or different and are C₁ to C₃ alkyl, and where halogen ischlorine, bromine or fluorine; or a pharmaceutically acceptable saltthereof.
 9. A neutrotropic composition of matter in dosage unit formcomprising from about 1 mg to about 250 mg per dosage of a compound asdefined in claim 1 in association with a pharmaceutically acceptablecarrier or diluent.
 10. A therapeutic composition of matter in dosageunit form for the treatment of anxiety or hypertension which comprises 5to 200 mg of a compound of claim 1 in association with apharmaceutically acceptable carrier or diluent.